Reversal of hippocampal neuronal maturation by serotonergic antidepressants
Reversal of hippocampal neuronal maturation by serotonergic antidepressants
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DOI：
10.1073/pnas.0912690107
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发表时间：
2010-05-04
影响因子：
11.1
通讯作者：
Suzuki, Hidenori
中科院分区：
文献类型：
--
作者：
Kobayashi, Katsunori;Ikeda, Yumiko;Suzuki, Hidenori
5-羟色胺能抗抑郁药常用于治疗情绪和焦虑障碍，越来越多的证据表明，这些药物的潜在用途超出了目前的抗抑郁药治疗。促进海马齿状回中的成年神经发生已被认为是抗抑郁药的候选作用机制，但该机制可能只是抗抑郁药的广泛作用之一。在这里，我们显示了一个独特的独特的行动，β-肾上腺素能抗抑郁药氟西汀在转化成熟的齿状颗粒细胞的表型。氟西汀长期治疗成年小鼠强烈降低了成熟颗粒细胞标志物钙结合蛋白的表达。氟西汀治疗诱导活跃的体细胞膜特性类似于未成熟的颗粒细胞，并显着降低突触促进的特征成熟的齿状回-CA 3信号传递。这些变化不能简单地用新产生的未成熟神经元的增加来解释，而最好的特征是成熟颗粒细胞的“去成熟”。这种颗粒细胞退化沿着5-HT 4受体依赖性神经调节中5-羟色胺功效的增加而发展，并且在缺乏5-HT 4受体的小鼠中减弱。我们的研究结果表明，多巴胺能抗抑郁药可以逆转成年海马神经元成熟的既定状态，5-HT 4受体介导的信号转导的上调可能在抗抑郁药的这种独特作用中发挥关键作用。这种神经元成熟的逆转可能会影响成熟海马回路的正常功能，但也可能通过恢复在发育过程中丢失的神经元功能而产生一些有益的影响。
Serotonergic antidepressant drugs have been commonly used to treat mood and anxiety disorders, and increasing evidence suggests potential use of these drugs beyond current antidepressant therapeutics. Facilitation of adult neurogenesis in the hippocampal dentate gyrus has been suggested to be a candidate mechanism of action of antidepressant drugs, but this mechanism may be only one of the broad effects of antidepressants. Here we show a distinct unique action of the serotonergic antidepressant fluoxetine in transforming the phenotype of mature dentate granule cells. Chronic treatments of adult mice with fluoxetine strongly reduced expression of the mature granule cell marker calbindin. The fluoxetine treatment induced active somatic membrane properties resembling immature granule cells and markedly reduced synaptic facilitation that characterizes the mature dentate-to-CA3 signal transmission. These changes cannot be explained simply by an increase in newly generated immature neurons, but best characterized as "dematuration" of mature granule cells. This granule cell dematuration developed along with increases in the efficacy of serotonin in 5-HT4 receptor-dependent neuromodulation and was attenuated in mice lacking the 5-HT4 receptor. Our results suggest that serotonergic antidepressants can reverse the established state of neuronal maturation in the adult hippocampus, and up-regulation of 5-HT4 receptor-mediated signaling may play a critical role in this distinct action of antidepressants. Such reversal of neuronal maturation could affect proper functioning of the mature hippocampal circuit, but may also cause some beneficial effects by reinstating neuronal functions that are lost during development.